Stimulus-responsive polymers are defined as polymers that undergo change in physical or chemical properties in response to small external change in an environmental parameter, for example pH, temperature or light. Stimulus-responsive polymers are also referred to as stimulus-sensitive, intelligent, smart, or environmentally-sensitive polymers.
Stimulus-responsive polymers have received increased attention due to their potential in various biological applications, including medical applications. Stimulus-responsive polymers have been designed to form various types of polymer assemblies, including cross-linked hydrogels, reversible hydrogels, micelles, modified interfaces and conjugated solutions. Application of these polymers in delivery of therapeutics, tissue engineering, bio-separation techniques, or as sensors or actuators has been reported, indicating the rapid progress of this field of research (Jeong et al. Trends. Biotechnol., 2002, 20, 305; Roy et al. Chemistry & Biology, 2003, 10, 1161; US 2006/0105001; US 2005/0169882; WO 2004/072258).
Response to stimulus is a basic process of living systems. Certain environmental conditions are seen in particular locales within the body, such as low pH and elevated temperature (Qiu et al. Adv. Drug. Deliv. Rev., 2001, 53, 321). Research has focussed on temperature and pH sensitive polymers, given that temperature and pH are relatively convenient and effective, as well as biologically relevant, stimuli.
Thus, pH and/or temperature sensitive polymers can be utilised for the preparation of ‘smart’ drug delivery systems that exploit variations in biological temperature and pH in order to effect site-specific controlled drug release.
Large differences in pH extensively exist in different organs, tissues, and cellular compartments. For example, along the GI tract, the pH changes from acidic in the stomach (pH 2) to more basic in the intestine (pH 5-8). As well, certain cancers, inflamed tissue and wound tissue exhibit a pH different than 7.4, which is the pH of blood circulation. In addition, pH drops from a range of pH 6.0-6.5 within the early endosome to a range of pH 5.0-6.0 within the late endosome and then to a range of pH 4.5-5.0 within the lysosome during cell endocytosis, resulting in a large change in proton concentration inside the various cellular compartments. Therefore, the pH variation within the body can be used to direct the response of a stimulus-responsive polymer when targeted to a particular tissue or cellular compartment. Polycations in non-viral gene therapy, acid triggered drug release systems in cancer targeting and polyanions and amphoteric polymers for endosomolytic delivery are some typical pH responsive polymers investigated in drug delivery (Schmaljohann, D. Adv. Drug. Deliv. Rev., 2006, 58, 1655).
Temperature is the most widely used stimulus in environmentally responsive polymer systems, given that temperature is relatively easy to control and is applicable both in vitro and in vivo. Poly-N-substituted acrylamides, for example poly(N-isopropylacrylamide) (PNIPAAm), polymers based on amphiphilic balance like poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO), and biopolymers and artificial polypetides like gelatin and agarose are some representative groups of temperature-responsive polymers (Gil et al. Prog. Polym. Sci., 2004, 29, 1173).
PNIPAAm is a commonly investigated stimulus-responsive polymer. This polymer is hydrophilic and soluble in aqueous solution below a lower critical solution temperature (LCST) of approximately 32° C. and becomes hydrophobic and insoluble above the LCST. However, PNIPAAm is not biodegradable, and thus would build up in the body if used for in vivo applications.
Polymers for use in biomedical applications generally require biocompatibility and biodegradability. For example, in drug delivery, biocompatible polymers have relatively low toxicity and biodegradable polymers can enhance sustained drug release and can reduce the need for surgical removal after drug depletion. Thus there still exists a need for development of additional stimulus-responsive polymers that are biocompatible and biodegradable.